Gel containing pirfenidone

ABSTRACT

The invention relates to a gel composition containing pirfenidone, which is advantageous over other cutaneously administered pharmaceutical forms known in the prior art and which can be used in treatment for the restoration of tissues with fibrotic lesions and for the prevention of fibrotic lesions.

RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 15/435,494 (allowed), filed on Feb. 17, 2017, which is adivisional application of U.S. patent application Ser. No. 13/893,626,filed on May 14, 2013, which is a divisional application of U.S. patentapplication Ser. No. 12/673,304, filed on Apr. 28, 2010 (now U.S. Pat.No. 8,492,412), which claims the benefit of and which is a nationalstage filing of International Application Serial No. PCT/MX2008/000107,filed on Aug. 14, 2008, which claims priority to, and the benefit of,Mexican Patent Application Serial No. MX/a/2007/009796, filed on Aug.14, 2007, the entire contents of both of which are hereby incorporatedby reference.

FIELD OF INVENTION

The present invention is related to a gel formula that containsPirfenidone, which offers advantages over other pharmaceutical forms ofknown cutaneous administration in the state of the technique.

BACKGROUND OF THE INVENTION

The 5-methyl-1-phenyl-2(1H)-pyridone, formula;

It is a drug that has been applied in the restoration of tissues withlesions with fibrosis and the prevention of fibrotic lesions. Thiscompound, Pirfenidone, it is by itself a known compound and itspharmacological effects has been described, for example, in Japaneseapplications numbers 87677/1974 and 1284338/1976, as ananti-inflammatory agent that includes antipyretic and analgesics. TheU.S. Pat. No. 3,839,346, published Oct. 1, 1974; the number 3, 974, 281,published Aug. 10, 1976; the U.S. Pat. No. 4,042,699 published Aug. 16,1977, and the U.S. Pat. No. 4,052,509 published Oct. 4, 1977, whichdescribed the methods for the obtained Pirfenidone, as well as its useas an anti-inflammatory agent. In the Mexican patent 182, 266 theantifibrotic activity of the 5-methyl-1-phenyl-2(1H)-pyridone isdescribed.

Different resources and treatments have been used to the date and noneof them have shown to be really effective. Pirfenidone has shown itsefficacy as an anti-fibrotic agent in different pathologies and organs,and has been demonstrated in previous works, where we have observed aneffect on the fibroblasts and the production of collagen andextracellular matrix, as well as in experimental models and in clinicaltests also.

Many substances could form gels when a gelificant agent is added. Thisis use in many diverse products in the manufacturing industry, from foodto paint, passing through adhesives.

Gels are also important in the chemistry part related with the processesSOL GEL and in the synthesis of solid materials with nanopores.

Gels are classified in: aqueous (hydrogels) or organic (organogels),dependingo if the aqueous component is water or an organic solvent;organic or inorganic in nature, colloidal or thick grain, according tothe size of the particles; and rigid gels, elastic or tixothrophic,according to its mechanic properties.

The hydrocolloids are substances that are produced from vegetable andanimal proteins or multiple sugars. They have the capacity to swellthemselves and to bind to water. The hydrocolloids are used to thicken,solidify and stabilize food.

OBJECT OF THE INVENTION

The object of the present invention is to provide a gel composition forits cutaneous administration that contains Pirfenidone, a viscous agent;a solubilizer; a non ionic solubilizer; a conserving agent; aneutralizer agent and purified water.

Also, it is the object of the present invention to provide a process ofmanufacture of a gel that contains pirfenidone for its cutaneousapplication.

Another objective of the present invention is to provide a gel medicineto be used as an anti-fibrotic and anti-inflammatory agent.

Specification of the Invention Composition of the Gel

The composition of the gel contains from 2 to 12% of Pirfenidone iselaborated utilizing from 0.4 to 1.2% of a viscous agent, from 10 to 30%of a solubilizer, from 5 to 15% of a non ionic solubilizer, from 0.2 to1% of a conserving agent, from 0.4 to 1.2% a neutralizer agent and therest of purify water. The viscous agent is selected from a carbomer 940(MR); Ultrex 10(MR), cellulose derivatives; gums; polioxameres; ethylicalcohol and propylenglycol; the conserving agent is selected from agroup that consist of Diazolidinyl urea, iodopropinil-butilcarbamate;methylparabene and a mix of these compounds; the neutralizer agent isselected from a group of primary, secondary and tertiary aliphaticamines of the mono-, bi- and triethanolamine type, and of the hydroxidealkaline metals, such as sodium hydroxide.

An example of the composition of the gel is shown in the table 1:

Component Quantity (g) % Pirfenidone 8 8 Viscous agent 0.5 0.5Solubilizer 20 20 Non ionic solubilizer 11.5 11.5 Conserving agent 0.50.5 Neutralizer 0.5 0.5 Purified water up to 100 59

The gel containing Pirfenidone is manufactured as follows:

-   -   a) Mix 50% of the total water to be used with the viscous agent,        allowing the complete humectation of the viscous agent;    -   b) Mix separately and with constant agitation the Pirfenidone        with the solubilizer agent;    -   c) Dissolve separately the non ionic solubilizer agent in the        25% water to be used at 40° C., once dissolved, the 15% of the        total water is added;    -   d) Add the solution from part c) to the mix from part b),        agitate until the mix is homogenate.    -   e) Dilute the neutralizer agent 10% of the total water to use,        agitate until the mix is homogenate; and    -   f) Add with constant agitation and homogenate in each addition        to the mix from part a) the solution from part d); the        conservative and the solution from part e).

A prepared composition according to procedure describe is shown in table2.

Component Quantity (g) Pirfenidone 8 Carbomer 0.5 N-methylpirrolidone 20Macrogolglycerol 11.5 Hidroxiestearate 40 Diazolidinilurea and 0.5Iodopropinil-butilcarbamate Triethanoalamine 0.5 Purified water up to100

These compositions are shown in an example mode, but they are notlimited in any level of the reach of the description of the presentinvention.

1-6. (canceled)
 7. A composition of pirfenidone gel comprising: (a)2-12% pirfenidone; (b) 0.4-1.2% of a viscous agent selected from thegroup consisting of Carbomer 940, Ultrex 10, cellulose derivatives,gums, and poloxamers; (c) 10-30% of a solubilizer selected from thegroup consisting of N-methylpyrrolidone, ethyl alcohol, and propyleneglycol; (d) 5-15% of a non-ionic solubilizer; (e) 0.2-1% of a conservingagent selected from the group consisting of diazolidinyl urea,iodopropynyl butylcarbamate, methylparaben, propylparaben, andcombinations of these conserving agents; (f) 0.4-1.2% of a neutralizeragent selected from the group consisting of primary, secondary andtertiary mono-, bi-, and triethanolamine aliphatic amines, and hydroxidealkaline metals; and (g) water.
 8. A method for preparing thecomposition of claim 7, the method comprising the steps of: (a) mixingapproximately 50% of the total water to be used with the viscous agentand allowing complete humectation of the viscous agent; (b) mixingpirfenidone and the solubilizer separately and with agitation; (c)dissolving separately the non-ionic solubilizer in approximately 25% oftotal water at approximately 40° C. and once dissolved, addingapproximately 15% of the total water; (d) adding the solution from part(c) to the mix from part (b), and agitating until homogenous; (e)diluting the neutralizer agent in approximately 10% of the total waterto be used, and agitating until homogenous; and (f) combining thesolutions of parts (a)-(e).
 9. The composition of claim 7, wherein theviscous agent is Carbomer
 940. 10. The method of claim 8, wherein theviscous agent is Carbomer
 940. 11. The composition of claim 7, whereinthe viscous agent is Ultrex
 10. 12. The composition of claim 7, whereinthe solubilizer is N-methylpyrrolidone.
 13. The composition of claim 7,wherein the solubilizer is propylene glycol.
 14. The composition ofclaim 7, wherein the non-ionic solubilizer is macrogolglycerolhydroxystearate
 40. 15. The composition of claim 7, wherein theconserving agent is diazolidinyl urea.
 16. The composition of claim 7,wherein the conserving agent is iodopropynyl butylcarbamate.
 17. Thecomposition of claim 7, wherein the conserving agent is methylparaben.18. The composition of claim 7, wherein the conserving agent ispropylparaben.
 19. The composition of claim 7, wherein the neutralizeragent is triethanolamine.
 20. The composition of claim 7, wherein theneutralizer agent is a hydroxide alkaline metal.
 21. The composition ofclaim 7, wherein the neutralizer agent is sodium hydroxide.
 22. Thecomposition of claim 7, wherein the viscous agent is Carbomer 940, thesolubilizer is N-methylpyrrolidone, the conserving agent is diazolidinylurea, and the neutralizer agent is triethanolamine.
 23. The compositionof claim 7, wherein the viscous agent is Carbomer 940, the solubilizeris N-methylpyrrolidone, the conserving agent is iodopropynylbutylcarbamate, and the neutralizer agent is triethanolamine.
 24. Thecomposition of claim 7, wherein the composition of pirfenidone gelcomprises: 8% pirfenidone, 0.5% of the viscous agent, 20% of thesolubilizer, 11.5% of the non-ionic solubilizer, 0.5% of the conservingagent, 0.5% of the neutralizer agent, and 59% of purified water.
 25. Thecomposition of claim 7, wherein the viscous agent is Carbomer 940, thesolubilizer is N-methylpyrrolidone, the non-ionic solubilizer ismacrogolglycerol hydroxystearate 40, the conserving agent isdiazolidinyl urea and iodopropynyl butylcarbamate, and the neutralizeragent is triethanolamine.
 26. A method for preventing fibrotic lesionsin a patient by administering to the patient the composition of claim 7.